tbuckley/cabot-search huggingface dataset:
Abstract CT115: Treatment of skin tumors with intratumoral interleukin 12 gene electrotransfer in the head and neck region: A phase I clinical trial
Authors: Gregor Sersa, Maja Cemazar, Crt Jamsek, Primoz Strojan, Tanja Jesenko, Masa Bosnjak, Ales Groselj
Journal: Cancer Research (2023)

Abstract Immunotherapies with monoclonal antibodies (checkpoint inhibitors) are currently being intensively researched and have led to excellent response in many cases in various tumors. Another potential approach to immunotherapy is the targeted intratumoral administration of interleukin 12 (IL -12), a cytokine with proven anti-tumor activity. Due to its immunomodulatory effect, it can be used as an immunostimulatory component for in situ vaccination of local ablative therapies. We have developed a phIL12 plasmid without antibiotic resistance markers using a transgene for the human IL -12 p70 protein. The plasmid can be introduced intratumorally by gene electrotransfer. In gene electrotransfer, electrical pulses are applied to the tumor to deliver the plasmid DNA into the cells. Based on nonclinical studies of safety, pharmacokinetics, pharmacodynamics, tolerability, and immunogenicity, a phase I clinical trial of phIL12 gene electrotransfer was conducted (ISRCTN15479959, ClinicalTrials NCT05077033). The primary objective of the study is to evaluate the safety and tolerability of phIL12 gene electrotransfer in the treatment of basal cell carcinoma in patients with operable tumors of the head and neck. The study, an exploratory, dose-escalating Phase I study, will enroll 9 patients in three dose-escalating cohorts. Treatment consists of plasmid injection followed by application of electrical pulses to the tumors. Patients are monitored for 30 days, with tumors removed if a complete response is not achieved. To date, two cohorts of patients have completed the study. No adverse effects or treatment-related toxicities have been observed, and treatment has been well tolerated by patients. The results of this study will provide the basis for the use of phIL12 gene electrotransfer as adjuvant therapy to local ablative therapies to enhance their local effect and elicit a systemic response. Citation Format: Gregor Sersa, Maja Cemazar, Crt Jamsek, Primoz Strojan, Tanja Jesenko, Masa Bosnjak, Ales Groselj. Treatment of skin tumors with intratumoral interleukin 12 gene electrotransfer in the head and neck region: A phase I clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT115.
Abstract CT056: A multicenter, open-label phase 1/2 trial evaluating the safety, tolerability, and efficacy of MORAb-202, a folate-receptor-alpha-targeting antibody-drug conjugate in patients with selected tumor types
Authors: Robert Wenham, Sharad Ghamande, Vicky Makker, June Hou, Linda Duska, Daniela Matei, Manali Bhave, Rachael Scott, Natalyn Hawk, Tingting Song, Deborah K. Armstrong
Journal: Cancer Research (2023)

Abstract Background: MORAb-202 (farletuzumab ecteribulin) is an antibody-drug conjugate (ADC) comprised of the humanized antifolate receptor-alpha (FRα) monoclonal antibody, farletuzumab, and the cytotoxic microtubule inhibitor, eribulin, conjugated by a cathepsin B-cleavable linker. MORAb-202 targets the eribulin payload to tumor cells expressing FRα, where internalization leads to lysosomal cleavage of the ADC and intracellular release of eribulin, causing apoptosis, cell-cycle arrest, and bystander effects in adjacent cells. A previous phase 1 study in Japan of MORAb-202 (NCT03386942) demonstrated antitumor activity across multiple tumor types and identified interstitial lung disease (ILD) as an adverse event of interest (Shimizu CCR 2021). An expansion cohort (doses: 0.9, 1.2 mg/kg) in patients with platinum-resistant ovarian cancer (OC) found meaningful efficacy across FRα-expression levels and ILD/pneumonitis (mainly low grade) was the most common adverse event (Nishio ASCO 2022). Methods: This multicenter phase 1/2 study (NCT04300556) consists of Dose-Escalation and Dose-Confirmation cohorts. In the Dose-Escalation phase, the primary objectives were to evaluate safety/tolerability and determine the recommended phase 2 dose of MORAb-202 in patients with OC, endometrial cancer (EC), non-small cell lung cancer (NSCLC), or triple-negative breast cancer (TNBC). In the ongoing Dose-Confirmation phase, the primary objectives are (1) to further evaluate safety/tolerability and (2) to evaluate preliminary efficacy (Objective Response Rate) in patients with OC or EC. Based on a population pharmacokinetics model (Hayato ASCO 2022), body-surface-area-based dosing is utilized. The initial cohort has enrolled 7 patients at a MORAb-202 25 mg/m2 IV Q3W dose and is ongoing; further enrollment of patients at 25 mg/m2 and 33 mg/m2 will occur following ILD safety evaluation. Tumor assessments will be conducted by investigators using RECIST v1.1 at screening, every 6 weeks for 24 weeks, then every 12 weeks or as needed. Assessments of computed tomography scans for ILD will be conducted by a central expert review board. Citation Format: Robert Wenham, Sharad Ghamande, Vicky Makker, June Hou, Linda Duska, Daniela Matei, Manali Bhave, Rachael Scott, Natalyn Hawk, Tingting Song, Deborah K. Armstrong. A multicenter, open-label phase 1/2 trial evaluating the safety, tolerability, and efficacy of MORAb-202, a folate-receptor-alpha-targeting antibody-drug conjugate in patients with selected tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT056.
Abstract CT099: First-in-human study of ALF501, polypeptide PSMA-targeted chimeric antigen receptor engineered natural killer cells) for castration-resistant prostate cancer
Authors: Hui Shi, Yanan Lin, Jie Ran, Yan Jin, Shengbang Zhang, Qi Wang, Huiyuan Zhang, Lida Wu, Yuchun Gu, Shengjiang Tan, Yao Wang
Journal: Cancer Research (2023)

Abstract Abstract Background: The mortality of castration-resistant prostate cancer (CRPC) is high due to lack of an effective treatment. Chimeric antigen receptor (CAR) based therapy is a promising immunotherapeutic strategy. In preclinical models, we established ALF501, a novel CAR-NK cells with both a high affinity for PSMA and a clinically significant tumoricidal effect on CRPC. Here we report the results from the first-in-human case of ALF501 for CRPC. Methods: In this study, ALF501was dosed intravenous for a total of three courses, with an interval of 3 months, each infusion of 5 × 108 cells, and 3 consecutive days of infusion as a course of treatment. Observation continued until progression or unacceptable toxicity for up to 1 years. Primary objectives were safety and tolerability; secondary objectives included preliminary antitumor activity. Results: An 80-year-old man who underwent laparoscopic radical prostatectomy in February 2018 and developed a relapse in April 2021. Starting with July 16 2021, he received three courses of ALF501. No liver and kidney toxicity was observed, and the safety profile was good. Progression-free survival was 12months as of April 23, 2022, during which PSA decreased by 97.5% from baseline. Imaging follow-up showed that the tumor was stable, and chest CT showed that the original pleural effusion and pericardial effusion disappeared, and the high-density shadow previously considered osteogenic bone metastasis was reduced overall. Conclusions: ALF501 is safe and feasible for the treatment of CRPC, and has preliminary anti-tumor efficacy. This is a case study, and it is necessary to expand the patient sample size in the future to confirm whether there is a difference in efficacy for different patients. Citation Format: Hui Shi, Yanan Lin, Jie Ran, Yan Jin, Shengbang Zhang, Qi Wang, Huiyuan Zhang, Lida Wu, Yuchun Gu, Shengjiang Tan, Yao Wang. First-in-human study of ALF501, polypeptide PSMA-targeted chimeric antigen receptor engineered natural killer cells) for castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT099.
Targeting a vulnerable septum-hippocampus cholinergic circuit in a critical time window ameliorates tau-impaired memory consolidation
Authors: Dongqin Wu, Nana Yu, Yang Gao, Rui Xiong, Luping Liu, Huiyang Lei, Sen Jin, Jiale Liu, Yingzhou Liu, Jiazhao Xie, Enjie Liu, Qiuzhi Zhou, Yanchao Liu, Shihong Li, Linyu Wei, Jingru Lv, Huilin Yu, Wenbo Zeng, Qiang Zhou, Fuqiang Xu, Min-Hua Luo, Yao Zhang, Ying Yang, Jian-Zhi Wang
Journal: Molecular Neurodegeneration (2023)

Abstract Background Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer’s disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive. Methods To investigate the effect and mechanism of the cholinergic circuit in Alzheimer's disease-related hippocampal memory, overexpression of human wild-type Tau (hTau) in medial septum (MS)-hippocampus (HP) cholinergic was achieved by specifically injecting pAAV-EF1α-DIO-hTau-eGFP virus into the MS of ChAT-Cre mice. Immunostaining, behavioral analysis and optogenetic activation experiments were used to detect the effect of hTau accumulation on cholinergic neurons and the MS-CA1 cholinergic circuit. Patch-clamp recordings and in vivo local field potential recordings were used to analyze the influence of hTau on the electrical signals of cholinergic neurons and the activity of cholinergic neural circuit networks. Optogenetic activation combined with cholinergic receptor blocker was used to detect the role of cholinergic receptors in spatial memory. Results In the present study, we found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. In addition to an inhibitory effect on neuronal excitability, theta synchronization between the MS and CA1 subsets was significantly disrupted during memory consolidation after overexpressing hTau in the MS. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm-dependent manner. Conclusions Our study not only reveals the vulnerability of a novel MS-CA1 cholinergic circuit to AD-like tau accumulation but also provides a rhythm- and time window-dependent strategy to target the MS-CA1 cholinergic circuit, thereby rescuing tau-induced spatial cognitive functions. Graphical Abstract
Molecular characteristics of breast tumors in patients screened for germline predisposition from a population-based observational study
Authors: Deborah F. Nacer, Johan Vallon-Christersson, Nicklas Nordborg, Hans Ehrencrona, Anders Kvist, Åke Borg, Johan Staaf
Journal: Genome Medicine (2023)

Abstract Background Pathogenic germline variants (PGVs) in certain genes are linked to higher lifetime risk of developing breast cancer and can influence preventive surgery decisions and therapy choices. Public health programs offer genetic screening based on criteria designed to assess personal risk and identify individuals more likely to carry PGVs, dividing patients into screened and non-screened groups. How tumor biology and clinicopathological characteristics differ between these groups is understudied and could guide refinement of screening criteria. Methods Six thousand six hundred sixty breast cancer patients diagnosed in South Sweden during 2010–2018 were included with available clinicopathological and RNA sequencing data, 900 (13.5%) of which had genes screened for PGVs through routine clinical screening programs. We compared characteristics of screened patients and tumors to non-screened patients, as well as between screened patients with ( n = 124) and without ( n = 776) PGVs. Results Broadly, breast tumors in screened patients showed features of a more aggressive disease. However, few differences related to tumor biology or patient outcome remained significant after stratification by clinical subgroups or PAM50 subtypes. Triple-negative breast cancer (TNBC), the subgroup most enriched for PGVs, showed the most differences between screening subpopulations (e.g., higher tumor proliferation in screened cases). Significant differences in PGV prevalence were found between clinical subgroups/molecular subtypes, e.g., TNBC cases were enriched for BRCA1 PGVs. In general, clinicopathological differences between screened and non-screened patients mimicked those between patients with and without PGVs, e.g., younger age at diagnosis for positive cases. However, differences in tumor biology/microenvironment such as immune cell composition were additionally seen within PGV carriers/non-carriers in ER + /HER2 − cases, but not between screening subpopulations in this subgroup. Conclusions Characterization of molecular tumor features in patients clinically screened and not screened for PGVs represents a relevant read-out of guideline criteria. The general lack of molecular differences between screened/non-screened patients after stratification by relevant breast cancer subsets questions the ability to improve the identification of screening candidates based on currently used patient and tumor characteristics, pointing us towards universal screening. Nevertheless, while that is not attained, molecular differences identified between PGV carriers/non-carriers suggest the possibility of further refining patient selection within certain patient subsets using RNA-seq through, e.g., gene signatures. Trial registration The Sweden Cancerome Analysis Network – Breast (SCAN-B) was prospectively registered at ClinicalTrials.gov under the identifier NCT02306096.
Abstract CT060: ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma
Authors: Isabel Arrillaga-Romany, Andrew Lassman, Susan L. McGovern, Sabine Mueller, Louis B. Nabors, Martin van den Bent, Michael Vogelbaum, Joshua E. Allen, Allen S. Melemed, Rohinton S. Tarapore, Dewen Yang, Patrick Wen, Timothy Cloughsey
Journal: Cancer Research (2023)

Abstract Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating dordaviprone in patients with H3 K27M-mutant disease. Methods: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023. Citation Format: Isabel Arrillaga-Romany, Andrew Lassman, Susan L. McGovern, Sabine Mueller, Louis B. Nabors, Martin van den Bent, Michael Vogelbaum, Joshua E. Allen, Allen S. Melemed, Rohinton S. Tarapore, Dewen Yang, Patrick Wen, Timothy Cloughsey. ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT060.
Associations of physical frailty with health outcomes and brain structure in 483 033 middle-aged and older adults: a population-based study from the UK Biobank
Authors: Rongtao Jiang, Stephanie Noble, Jing Sui, Kwangsun Yoo, Matthew Rosenblatt, Corey Horien, Shile Qi, Qinghao Liang, Huili Sun, Vince D Calhoun, Dustin Scheinost
Journal: The Lancet Digital Health (2023)
First-in-patient study of OTL78 for intraoperative fluorescence imaging of prostate-specific membrane antigen-positive prostate cancer: a single-arm, phase 2a, feasibility trial
Authors: Judith A Stibbe, Hilda A de Barros, Daan G J Linders, Shadhvi S Bhairosingh, Elise M Bekers, Pim J van Leeuwen, Philip S Low, Sumith A Kularatne, Alexander L Vahrmeijer, Jacobus Burggraaf, Henk G van der Poel
Journal: The Lancet Oncology (2023)
Effectiveness of a bivalent mRNA vaccine booster dose to prevent severe COVID-19 outcomes: a retrospective cohort study
Authors: Ronen Arbel, Alon Peretz, Ruslan Sergienko, Michael Friger, Tanya Beckenstein, Hadar Duskin-Bitan, Shlomit Yaron, Ariel Hammerman, Natalya Bilenko, Doron Netzer
Journal: The Lancet Infectious Diseases (2023)
Efficacy against pneumococcal carriage and the immunogenicity of reduced-dose (0 + 1 and 1 + 1) PCV10 and PCV13 schedules in Ho Chi Minh City, Viet Nam: a parallel, single-blind, randomised controlled trial
Authors: Beth Temple, Hau Phuc Tran, Vo Thi Trang Dai, Heidi Smith-Vaughan, Paul Vincent Licciardi, Catherine Satzke, Thuong Vu Nguyen, Kim Mulholland, Anne Balloch, Jemima Beissbarth, Kathryn Bright, Rachel Ann Higgins, Jason Hinds, Pham Thi Hoan, Monica Larissa Nation, Cattram Duong Nguyen, Belinda Daniela Ortika, Thanh V Phan, Tran Linh Phuong, Leena Spry, Ho Nguyen Loc Thuy, Nguyen Trong Toan, Doan Y Uyen, Le Thi Tuong Vy
Journal: The Lancet Infectious Diseases (2023)

Interest in reduced-dose pneumococcal conjugate vaccine (PCV) schedules is growing, but data on their ability to provide direct and indirect protection are scarce. We evaluated 1 + 1 (at 2 months and 12 months) and 0 + 1 (at 12 months) schedules of PCV10 or PCV13 in a predominately unvaccinated population.
Hybrid immunity against reinfection with SARS-CoV-2 following a previous SARS-CoV-2 infection and single dose of the BNT162b2 vaccine in children and adolescents: a target trial emulation
Authors: Sivan Gazit, Yaki Saciuk, Galit Perez, Asaf Peretz, Amir Ben-Tov, Elizabeth A Stuart, Tal Patalon
Journal: The Lancet Microbe (2023)

Although most children and adolescents have had a previous SARS-CoV-2 infection and many continue to receive COVID-19 vaccinations, studies of the effectiveness of hybrid immunity against reinfection with the omicron (B.1.1.529) variant are scarce. We aimed to examine the effectiveness of vaccination in convalescent children and adolescents against reinfection with the delta (B.1.617.2) variant and the BA.1 and BA.2 and BA.4 and BA.5 omicron subvariants.
The relationship between CD4+ T cell glycolysis and their functions
Authors: Siyi Liu, Shan Liao, Lin Liang, Jun Deng, Yanhong Zhou
Journal: Trends in Endocrinology and Metabolism (2023)

CD4+ T cells are effector T cells (Teffs) produced by the differentiation of initial T cells in peripheral lymphoid tissue after being attacked by antigens, and have an indispensable role in the development and activation of B cells and CD8+ T cells to regulate and assist immunity. In this review, we provide a new perspective on the relationship between CD4+ T cell glycolysis and its function. We summarize the effects of changes in the glycolysis level of CD4+ T cells on their activation, differentiation, proliferation, and survival. In addition, we emphasize that regulation of the glycolysis level of CD4+ T cells changes their inflammatory phenotypes and function. The study of immune metabolism has received more attention recently, but more work is needed to answer many open questions.
Redefining Clostridioides difficile infection antibiotic response and clinical outcomes
Authors: Anne J Gonzales-Luna, Andrew M Skinner, Carolyn D Alonso, Emilio Bouza, Oliver A Cornely, Tim G J de Meij, Richard J Drew, Kevin W Garey, Dale N Gerding, Stuart Johnson, Stacy A Kahn, Haru Kato, Ciaran P Kelly, Colleen R Kelly, Larry K Kociolek, Ed J Kuijper, Thomas Louie, Thomas V Riley, Thomas J Sandora, Maria J G T Vehreschild, Mark H Wilcox, Erik R Dubberke
Journal: The Lancet Infectious Diseases (2023)
Long-acting antiretrovirals and HIV treatment adherence
Authors: Jean B Nachega, Kimberly K Scarsi, Monica Gandhi, Rachel K Scott, Lynne M Mofenson, Moherndran Archary, Sharon Nachman, Eric Decloedt, Elvin H Geng, Lindsay Wilson, Angeli Rawat, John W Mellors
Journal: The Lancet HIV (2023)